This invention relates to materials useful as antibacterial agents in humans and other animals, and compositions containing such materials. In particular, it relates to a novel crystalline form of nitrofurantoin.
Nitrofurantoin is an antibacterial agent used extensively in the treatment of urinary tract infections. It is rapidly absorbed in the gastrointestinal tract, and reaches high concentrations in the urine. A general description of nitrofurantoin is found in D. E. Cadwallader, 15 J. American Pharmaceutical Association 409 (1975); and J. D. Conklin, "The Pharmacokinetics of Nitrofurantoin and Its Related Bioavailability," 25 Antibiotics and Chemotherapy 233 (1978).
As with many other pharmaceutical active materials, the pharmacokinetics of nitrofurantoin may be affected by the size and type of nitrofurantoin crystals used in a dosage form. See, for example, J. K. Haleblian, "Characterization of Habits and Crystalline Modification of Solids and Their Pharmaceutical Applications", 66 J. Pharmaceutical Sciences 1269 (1975). In particular, the use of macrocrystalline nitrofurantoin has been found to reduce the level of emetic side effects that may be associated with nitrofurantoin. This association is discussed in the following articles: H. E. Paul et al., "Laboratory Studies with Nitrofurantoin", 56 J. Pharmaceutical Sciences 882 (1967), and N. Garti et al., "Habit Modifications of Nitrofurantoin Crystallized from Formic Acid Mixtures", 6 Drug Development and Industrial Pharmacy 379 (1980). Macrocrystalline nitrofurantoin having a surface area of from 120 cm.sup.2 /g (0.012 M.sup.2 /g) to 1000 cm.sup.2 /g (0.1 M.sup.2 /g) is described in U.S. Pat. No. 3,401,221, Borgmann et al., issued Sep. 10, 1968.
Nitrofurantoin is marketed by Norwich Eaton Pharmaceuticals, Inc., in several dosage forms using nitrofurantoin of differing crystal size. One such dosage form is a suspension of nitrofurantoin monohydrate. The crystals of nitrofurantoin in these suspensions are fine particles typically smaller than about 170 mesh. Another solid dosage form contains relatively large crystals of anhydrous nitrofurantoin (from about 40 to about 200 mesh), in a capsule (marketed under the tradename "Macrodantin"). The BET surface area of these macrocrystals is from about 0.06 M.sup.2 /g to about 0.15 M.sup.2 /g.
A variety of dosage forms of nitrofurantoin are also known in the pharmaceutical literature. For example, solid oral dosage forms of nitrofurantoin are described in U.S. Pat. No. 4,122,157, Huber, issued Oct. 24, 1978; U.S. Pat. No. 4,370,313, Davies, issued Jan. 25, 1983; European Patent Publication 250,023, Patel et al., published Dec. 23, 1987; and European Patent Publication 250,038, Patel, published Dec. 23, 1987. Suspensions of nitrofurantoin are described in N. Shah et al., "Effect of Polymers on Dissolution from Drug Suspensions", 65 J. Pharmaceutical Sciences 1618 (1976).
None of these references, however, describes an aqueous suspension of macrocrystalline nitrofurantoin. Such a suspension would combine the highly desirable pharmacokinetics of commercially available macrocrystalline nitrofurantoin capsules (Macrodantin), with the benefits of pharmaceutical suspensions. Suspensions may be desirable, for example, for treatment of patients who are unable to swallow capsule or tablet dosage forms. Also, suspensions may facilitate treatment of gastrointestinal disorders, providing rapid and even dispersion of the pharmaceutical active in gastric fluids.